Lower alkyl-a



United States Patent This invention relates to new diphenyl methane derivatives, which possess strong analgesic properties, and to methods for preparing the same.

In our co-pending patent application Serial No. 845,068 there are described derivatives of diphenyl methane having the general formula:

wherein Y represents a CN, CONH COOH, COOM, COOR, COOR COR or CON group; where M is an alkali metal, R is QDN n being an integer less than 4, R is a lower alkyl group, and R and R are lower alkyl groups optionally substituted, which groups may form together with the nitrogen atom attached thereto a saturated heterocyclic ring optionally containing a further nitrogen atom or an oxygen atom; and wherein A represents either a 2-, 3- or 4- pyridyl group, each optionally substituted by a lower alkyl group, or, when Y represents a COOR group, a phenyl group optionally substituted by one or more chlorine or bromine atoms or alkyl or alkoxy groups containing up to 5 carbon atoms.

According to one aspect of the present invention, there are provided derivatives of diphenyl methane having the general formula:

COORi CHI L.

are provided methods for preparing the compounds having the general Formula II above.

When R and R are both hydrogen, the compounds are prepared and handled as their salts, since the free bases are unstable and cyclise immediately. However, when R is a lower alkyl group, the free bases are stable and may be converted to the salts of any therapeutically acceptable non-toxic acid.

, 3,128,277 Patented Apr. 7, 1964 Q COORI wherein R and R have the meanings previously defined. Compounds having the general Formula III and their method of preparation are described in our previously mentioned copending patent application. The reduction of compounds of the general Formula III may be carried out in dry methanol or ethanol by reacting the compound in the form of a salt, preferably the hydrochloride, with hydrogen in the presence of Adams platinum catalyst at a temperature in the range of from 2050 C. and at a pressure of from one to ten atmospheres. The reduced compounds are advantageously isolated as their non-toxic acid addition salts, preferably the hydrochloride, since when R; is a hydrogen atom the free bases cyclise immediately.

To obtain compounds of the general Formula II when is a methyl group, the reduced compounds prepared in the above manner may be methylated, either by methylation of an ethanolic solution of a salt thereof, preferably the hydrochloride, in the presence of formaldehyde using Adams platinum catalyst and hydrogen, or more advantageously by heating an aqueous solution of the salt, preferably the hydrochloride, with formic acid, formaldehyde and sodium formate. The resulting N- methyl compounds are obtained as the free base, which may be converted to the corresponding salt of any therapeutically acceptable non-toxic acid.

The following non-limitative examples illustrate the invention.

Example 1 Example 2 Methyl 1:1-diphenyl-2-(2'-piperidinyl) propionate hydrochloride (4.4 g.), water (5 mls.), formic acid (1.0 ml.), sodium formate (1.3 g.) and aqueous formaldehyde (40%, 1.6 mls.) were heated together under reflux for seven hours. After cooling, the solution was basified with 5 N sodium hydroxide and the precipitated oil was extracted with ether. The ether solution was extracted with normal hydrochloric acid three times. The combined extracts were washed twice with ether then basified with sodium hydroxide solution. The precipitated oil was scratched until it crystallised and was then collected and washed with water. Recrystallisation from methanol gave methyl 1:1-diphenyl-2-(2-(1-methyl piperidinyl)) propionate as prisms, having a melting point of 126-128 C. The hydrochloride, formed in ether, had a melting point of l68-l70 C. (d) after crystallisation from a mixture of methanol and ether.

Example 3 Methyl 1:l-diphenyl-2-(2(6'-methyl pyridyl)) propionate hydrochloride (7.0 g.) dissolved in dry methanol (80 mls.) was shaken with hydrogen and Adams platinum catalyst at atmospheric pressure and room temperature for five hours, when hydrogen uptake ceased. The catalyst was removed by filtration and most of the methanol was distilled 01f. Addition of ether to the solution gave a voluminous precipitate of small white needles which were recrystallised from methanol-ether to give methyl 1:1-diphenyl-2-(2'-(6'-rnethyl piperidinyl)) propionate hydrochloride of melting point 226- 227 C. (d).

Example 4 Ethyl 1:l-diphenyl-Z-(2'-pyridyl) propionate hydrochloride (7.0 g.) was dissolved in dry ethanol (120 mls.) by warming and was shaken with hydrogen and Adams platinum catalyst at atmospheric pressure. After one hour some precipitation occurred so the solution was warmed to 50, when the precipitate redissolved, and hydrogenation was continued. After six hours the theoretical amount of hydrogen had been taken up and absorption ceased. The catalyst was filtered off and most of the ethanol was distilled off. Addition of acetone and then ether gave ethyl 1: 1-diphenyl-2-(2-piperidinyl) propionated hydrochloride, melting point 170-173 C. which was raised to 173-1745 C. by crystallisation from an ethanol-ether mixture. The free base is unstable and cyclises immediately.

Example 5 Ethyl 1: l-diphenyl 2-(2'-(6-methyl pyridyl)) propionate hydrochloride (7.0 g.) in dry ethanol (100 mls.) was shaken with hydrogen and Adams platinum catalyst at atmospheric pressure and room temperature. The re duction was complete in five hours. After filtering off the catalyst, most of the ethanol was distilled ofif and ether was added. Ethyl 1:1-diphenyl-2-(2-(6-methyl piperidinyl)) propionate hydrochloride crystallised out; this compound when recrystallised from an ethanol-ether mixture had a melting point of 216218 C. (d).

Example 6 Ethyl 1:1-diphenyl-2-(2'-piperidinyl) propionate hydrochloride (3.4 g.), water (5 mls.), formic acid (0.8 ml.), sodium formate (1.0 g.) and aqueous formaldehyde (40%, 1.2 mls.) were refluxed together for five hours. After cooling, the solution was made strongly basic with 5 N sodium hydroxide and the precipitated oil was extracted with ether. The ether solution was extracted with normal hydrochloric acid three times, and then the combined acid extracts were washed twice with ether and basified with sodium hydroxide solution. The precipitated oil solidifiedon scratching and was collected, washed with water, dried, and recrystallised from petroleum ether (B.P. (SO-80 C.) to give colourless prisms of ethyl 1:1- diphenyl-2-(2'-(1-methyl piperidinyl)) propionate, having a melting point of 74-76 C.

The hydrochloride, formed in ether, had a melting point of 138-141 C. after crystallisation from a mixture of ethanol and ether.

We claim:

1. A compound selected from the group consisting of compounds having the formula:

C-CH; N R

wherein R is lower alkyl, R is a radical selected from the group consisting of hydrogen and lower alkyl, and R is methyl, which process comprises heating with formic acid, formaldehyde and sodium formate an aqueous solution of salt of a compound of the formula defined in claim 1, wherein R is lower alkyl, R is a radical selected from the group consisting of hydrogen and lower alkyl, and R is a hydrogen.

References Cited in the file of this patent UNITED STATES PATENTS 2,649,455 Walter et al Aug. 18, 1953 2,713,050 Walter et al July 12, 1955 2,713,051 Walter et al July 12, 1955 2,742,397 Ott Apr. 17, 1956 2,799,679 Eckenstam et al. July 16, 1957 2,855,342 Wagner et al. Oct. 7, 1958 2,976,291 Jacob et al Mar. 21, 1961 FOREIGN PATENTS 775,376 Great Britain May 22, 1957 OTHER REFERENCES Richters Organic Chemistry, volume 3, pages 3 to 4 (1923), P. Blakistons Son and Co.

Zaugg et al.: J. Am. Chem. Society, volume 75, page 291 (1953).

Biel et al.: J Am. Chem. Society, volume 77, page 2251 (1955). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 